The goal of this research program is to improve drug therapy for, and gain insight into cardiovascular diseases; with emphasis on hypertension, as well as myocardial infarction, arrhythmias, and failure. Three closely related lines of investigation are pursued. The first involves basic and clinical studies of the efficacy, toxicity, disposition, optimal dosage regimens, and molecular basis of action of both current and new antihypertensive and cardioactive drugs. The second involves basic and clinical studies of selected enzymes (sodium potassium ATPase, renin and kallikrein) and vasoactive substances (catecholamines, prostaglandins and peptides) thought to be involved in the genesis and sequelae of hypertension. The third line of investigation represents a combination of the first two, namely, basic and clinical studies of the relationships between the effects of selected cardiovascular drugs on vasoactive substances and enzymes and the course of the diseases under study. Additional studies are aimed at defining the molecular mechanisms underlying adverse cytotoxic drug reactions as a basis for development of specific treatment regimens and as a guide for new drug development. This research emphasizes the use of molecularly specific analytical techniques and will involve work with artificial and natural cell membranes, isolated cardiac and vascular smooth muscle, liver, kidney, and other cells, isolated vascular and adrenergic tissues, isolated hearts, kidneys, limbs, whole animals, animal models of disease and normal and patient volunteers. In addition to well equipped bench research laboratories, facilities include a University General Clinical Research Center, a Clinical Pharmacology Outpatient Research Clinic, a General Internal Medicine Ward, core mass spectrometry, electron microscopy and synthetic organic chemistry laboratories, machine and electronic shops. This research is done by an integrated and interdisciplinary group of biochemical, physiological and clinical pharmacologists, chemists, cardiologists, radiologists, endocrinologists, biometricians, pharmacists and pathologists.